With a goal of creating living tissue prosthetics, Jonathan Butcher wants to understand how very socially engaged cells make choices about interacting with and manipulating their environment—constituting a naturally engineered system.

“Instead of making something out of plastic and metal that is one size, causes problems with the host’s immune system, and can’t sense its environment or respond to it, we said why don’t we follow up on earlier researchers’ ideas to make a living tissue replacement?”

Jesse Winter

Jesse Winter

Living Prosthetics, Naturally Engineered

What if diseased body parts, such as heart valves, could be replaced with living tissue that grows and changes along with the body?

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The ability to engineer living prosthetic replacements for diseased body parts may sound like the premise of a science fiction story, but if Jonathan T. Butcher, Meinig School of Biomedical Engineering, has his way, engineered tissue may become common in the future. For that to happen, Butcher says that researchers have to fully understand the biological processes that create tissue in the first place. He is working toward that goal by focusing on what he calls natural engineering—the idea that the tissues in the body evolve into complex structure, composition, and anatomy through interactions between cells and their environment rather than cells following a genetic blueprint by rote.

“A lot of people study embryonic development as a purely genetic process,” Butcher says. “In this view, the cells in your body are single-mindedly reading an instruction booklet that’s teaching them what to be. In our view, the cells are very social, very environmentally engaged beings that make choices based on how they interrogate their environment, with gene transcription being just one of the tools they use to manipulate that environment.” These choices comprise an engineering system. Butcher explains, “Our goal is to understand how that system works, so that we can potentially diagnose or fix problems through manipulating it.”

Manipulating Our Cells’ Natural Engineering System to Treat Disease

While investigating the system, Butcher and his coresearchers discovered that certain components of adult onset diseases have an origin in development. “I’m not talking about just the presence of an underlying genetic defect,” he says. “I’m talking about a predisposition of these cells toward reactivating developmental programs.” This happens if the cells’ environment pushes them to change in a way that the cells remember from early development.

Butcher gives an example of the heart valve, the tissue his lab studies most. Valves have very thin tissues that keep the blood flowing in one direction. The cells that line the surface of these tissues, called endothelial cells, have the capacity to transform into a different type of cell, one that wants to be surrounded by cell matrix below the surface. “This process is fundamental in forming valves in the first place,” says Butcher. “But it stops in adulthood.” In the case of a disease called aortic valve stenosis, however, the adult endothelial cells differentiate into an undesirable phenotype, bone, causing calcification of the valves. Instead of being flexible, the valve tissue becomes crusty and hard and no longer opens and closes as it should.

Using their knowledge of the programs a developing heart follows to naturally engineer a valve, the researchers hope to come up with a way to treat the underlying mechanism of the disease. “We are investigating both pathways that suggest susceptibility and those that suggest resistance to these programs,” Butcher says. “We have an idea of how to fix these cells by altering their mechanical sensation.” The cells originally responded to their environment to become the unwanted crusty tissue, the researchers reason, so perhaps they can manipulate the cells’ environment in such a way as to trick them into returning to their normal flexible state. “It’s a very different way of treating a disease,” Butcher says.

“There is a huge amount of challenges. But if we utilize the engineering strategies we learned from development in the first place, we sort of have a blueprint to construct that tissue.”

For the Heart—Living Tissue Prosthetics

The Butcher Lab is also breaking new ground in engineering living prosthetic replacements. “Instead of making something out of plastic and metal that is one size, causes problems with the host’s immune system, and can’t sense its environment or respond to it, we said why don’t we follow up on earlier researchers’ ideas to make a living tissue replacement?” Butcher explains. Again, his focus is the heart valve, an extremely complex tissue. “There is a huge amount of challenges. But if we utilize the engineering strategies we learned from development in the first place, we sort of have a blueprint to construct that tissue.”

Given how intricate the valve is, Butcher has settled on a complex fabrication methodology: three-dimensional (3D) tissue printing. Cornell is a leader in this technology, spearheaded in the early 2000s by Lawrence Bonassar, Biomedical Engineering/Mechanical and Aerospace Engineering, and former Cornell professor Hod Lipson, now at Columbia University. Butcher was won over from his initial skepticism of 3D printing when he joined Cornell and had an office next door to Bonassar and Lipson. “My problems were very different from theirs,” he says, “but when I saw how well it was working for Larry and Hod, I realized this could really work for me too.”

The Butcher Lab has succeeded in making a valve, using high-resolution micro-CT (a type of 3D x-ray scanning) to obtain a detailed understanding of the geometry of the valve as well as 3D printing of soft-tissue hydrogel deposited in a computer-controlled manner to fabricate it. They have the ability to not only fabricate macroscale anatomy but also to fine-tune the microenvironment within the macroscale. “Imagine someone making a vase out of clay,” Butcher explains. “They have to shape it, but then they also paint it, and every jot in every little location is very important. In the case of the heart valve, just making the shape isn’t enough. We have to make it out of more than one material. It has to be stiff in some places and soft in others. It has to have very complex shapes, and it has to be populated by very different cell types in different areas.”

A Potential Option for Congenital Valve Disease

So far, the researchers have tested their heart valve in a bioreactor that simulates blood flow pulses, similar to what occurs in a body. The next step will be to test the engineered valve in animal models. If those are successful, 3D-printed living valves may one day be the norm. This will be especially important for young people born with congenital valve disease. Current prosthetic valves have been developed for the elderly and don’t work for children and young adults for a host of reasons, including the prosthetic’s inability to grow with the patient and the limits of its capacity to handle large swings in heart rate that are typical of young, active people.

Developing a new, groundbreaking approach to treating congenital valve disease is the type of research perfectly suited for an academic research institution like Cornell, according to Butcher. He says, “Currently no company is going to take this on. The science is not known. The engineering technology is not yet available. The only thing that’s known is the need. We’ve tried a lot of different things for these patients, but it’s still a wide-open problem. It will take collaborative partnerships between engineering, life science, chemistry, clinicians, and industry experts to bring this from the bench to the bedside. Fortunately, Cornell is very strong in all of these areas, so we have a good chance to bring this forward.”